Atomoxetine HCl is a selective norepinephrine reuptake inhibitor. It is marketed under the name STRATTERA® for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD) and is available in 10 mg, 18 mg, 25 mg, 40 mg, and 60 mg dosage forms.
Atomoxetine, chemically known as (R)-(−)-N-methyl-3-(2-methylphenoxy)-3-phenylpropylamine; has the following structure:

Atomoxetine, the (R)-(−) enantiomer of tomoxetine, is a aryloxyphenylpropylamine. It is about twice as effective as the racemic mixture and about nine times more effective than the (+)-enantiomer, as disclosed in U.S. Pat. No. 4,018,895 (assigned to Eli Lilly and Co.), EP 0 052 492 (Eli Lilly and Co.), and EP 0 721 777 (Eli Lilly and Co.).
Several processes for synthesizing 3-aryloxy-3-phenylpropylamines are known in the art. For example, U.S. Pat. No. 4,018,895 assigned to Eli Lilly and Co. discloses an aliphatic nucleophilic displacement of N-protected-3-halogen-3-phenylpropylamines by phenols, followed by N-deprotection. U.S. Pat. No. 4,868,344 assigned to Aldrich-Boranes, Inc. relates to the Mitsunobu reaction between 3-hydroxy-3-phenylpropylhalides and phenols, followed by amination of the resulting 3-aryloxy-3-phenylpropylhalides. Tomoxetine is also synthesized by the processes disclosed in U.S. Pat. No. 6,541,668 and WO 00/58262 (assigned to Eli Lilly and Co.) and WO 94/00416 (by Richter Gedeon Vegyeszeti Gyar RT). These documents disclose an aromatic nucleophilic displacement of an aryl halide by 3-hydroxy-3-phenylpropylamines under strongly basic conditions. The nucleophilic aromatic displacement process disclosed in WO 00/58262 includes reacting N-methyl-3-hydroxy-3-phenylpropylamine with a protected 2-fluorobenzaldehyde to produce tomoxetine after several functional group interconversion steps.
EP Patent No. 0 052 492 discloses a process for the preparation of atomoxetine HCl. In this process, (R)-(−)-tomoxetine (S)-(+)-mandelate is first basified in water to eliminate the mandelate, then extracted in diethyl ether. HCl gas is bubbled into the solution to obtain (R)-(−)-tomoxetine (atomoxetime) hydrochloride. Yields are reported as approximately 77%-90%.
Similarly, U.S. Pat. No. 6,541,668, assigned to Eli Lilly and Co., discloses a process for the preparation of atomoxetine HCl involving basifying the mandelate salt, followed by extracting with t-butyl methyl ether, removing water by azeotropic distillation, and adding hydrogen chloride. This process is inefficient due to long process time, low product yields, and the use of hazardous solvents that are incompatible with large-scale industrial synthesis.
Thus, there is a need in the art for processes for the preparation of atomoxetine hydrochloride that will produce higher yields and that will facilitate commercial production.